# LDLRAD3 Receptor Interaction with Venezuelan Equine Encephalitis Virus

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $762,686

## Abstract

Project Summary
Alphaviruses are mosquito-transmitted, positive-strand enveloped RNA viruses of the Togaviridae family that
cause global disease in humans. At present, no antiviral agents or licensed vaccines exist for the treatment or
prevention of any alphavirus infections. We recently used a genome-wide CRISPR/Cas9-based screen to identify
the cell surface molecule LDLRAD3 as a novel, highly conserved entry receptor for Venezuelan equine
encephalitis virus (VEEV), an emerging pathogen capable of causing fatal neuroinvasive disease in humans and
other vertebrate animals. Gene editing of mouse or human LDLRAD3 resulted in reduced VEEV infection of
neuronal cells, and reciprocally, ectopic expression of LDLRAD3 resulted in increased infection. LDLRAD3
bound directly to VEEV virions and enhanced virus attachment and internalization into cells. Genetic studies
indicated that domain 1 (D1) of LDLRAD3 is necessary and sufficient to support VEEV infection. We hypothesize
that engagement of LDLRAD3 by VEEV will explain how infection, tissue targeting, and disease pathogenesis
occurs. The primary goals of this collaborative, interactive project between the Diamond, Fremont, and Whelan
laboratories are to define the precise mechanism(s) by which LDLRAD3 facilitates alphavirus entry into cells, to
gain high-resolution structural insight as to how LDLRAD3 engages the spike proteins on the virion, and to
determine the cell-type specific role of LDLRAD3 in VEEV pathogenesis in vivo. The experiments in this proposal
will define fundamental aspects of VEEV biology that enhance our understanding of infection and cell tropism.
This information may facilitate the development of small molecules or biologicals that disrupt LDLRAD3
interaction with VEEV spike proteins, which could form the basis of future therapeutics that ameliorate disease
of this emerging and highly pathogenic alphavirus.

## Key facts

- **NIH application ID:** 10867410
- **Project number:** 5R01AI164653-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Michael S Diamond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $762,686
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867410

## Citation

> US National Institutes of Health, RePORTER application 10867410, LDLRAD3 Receptor Interaction with Venezuelan Equine Encephalitis Virus (5R01AI164653-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10867410. Licensed CC0.

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